Methods for coating and impregnating medical devices with antiseptic compositions

ABSTRACT

The present invention provides methods of coating or impregnating medical devices with an antiseptic composition that will inhibit or prevent the nosocomial infections typically associated with the use of such medical devices. The present invention further provides methods of coating or impregnating medical devices that produce devices with effective activity against infection, while avoiding destroying the devices or causing the devices to become toxic. In addition, the invention provides medical devices coated or impregnated with antiseptic compositions by the aforementioned novel methods.

The present application claims benefit of priority to U.S. Provisional Application Ser. No. 60/538,284, filed Jan. 20, 2004, the entire contents of which are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to the field of microbiology. More particularly it provides novel methods for coating or impregnating medical devices such as catheters, tubes, stents, and sutures with antiseptic compositions in order to prevent the growth of pathogens in such devices and hence, to prevent infection to patients via such devices. In addition, the invention provides medical devices coated or impregnated with antiseptic compositions by the aforementioned novel methods.

2. Description of Related Art

Most nosocomial infections are caused by the contamination of medical devices resulting in serious hospital-acquired infections. Nosocomial pneumonias are the second most common nosocomial infections, and are associated with the highest attributable mortality and morbidity. Recent data have shown that at least 300,000 episodes of nosocomial pneumonia occur annually in the United States (Official Statement, American Thoracic Society). The attributable mortality of this infection is 33%-50%, hence, around 100,000 patients die annually because of nosocomial pneumonia (CDC, 1993; Leu et al., 1989). The risk of nosocomial pneumonia increases 6- to 20-fold from the use of mechanical ventilation (Official Statement, American Thoracic Society).

The endotracheal tube is considered a common vehicle for colonization/contamination leading to nosocomial pneumonia. The endotracheal tube connects the oropharyngeal environment with the sterile bronchoalveolar space, significantly increasing the risk of nosocomial pneumonia. Endotracheal tubes are typically constructed of polyvinylchloride, which is known to be very difficult to impregnate with antiseptic or antimicrobial agents. Thus, there are no endotracheal tubes that are impregnated with antibiotics or antiseptics currently in use.

Another leading cause of serious nosocomial infections is bloodstream infections. The primary contributors to nosocomial bloodstream infections are vascular catheters. It is estimated that around 400,000 vascular catheter-related bloodstream infections (CRBSI) occur annually in the United States (Raad, 1998). The attributable mortality of these infections in the intensive care unit (ICU) was estimated in JAMA in 1994 to be 25% (Reiselman et al., 1994). Hence, these infections are a major cause of morbidity and mortality in hospitalized patients. These catheters are mostly polyurethane short-term catheters used in the ICU and long-term silicone catheters used in cancer/AIDS patients.

The most frequent causes of nosocomial infections are urinary tract infections (UTI), contributing to 34% of all nosocomial infections (Klempner et al., 1998). Nosocomial UTI are usually associated with contamination of urinary catheters. In addition, nosocomial surgical wound infections are common complications of surgical procedures, particularly in cancer and immunocompromised patients with devitalized tissue and decreased immunity. Surgical wound infections contribute to 17% of all nosocomial infections (Platt and Bucknall, 1988). Many surgical wound infections are associated with the contamination of sutures.

Antibiotics are strictly antibacterial agents that are usually used in treatment of systemic or bloodstream infections and are given through oral, intravenous, subcutaneous, or intramuscular routes to achieve systemic bloodstream levels. Examples include penicillin, cephalosporins, vancomycin, minocycline, and rifampin.

Antiseptics on the other hand, are antimicrobial agents often with broad spectrum antimicrobial activity against bacteria, fungi or viurses. These agents are used on the skin and external mucosal surfaces usually because of limitations related to absorption, penetration or systemic toxicity. These agents are not used in the treatment of bloodstream infections. Examples include chlorhexidine and povidone iodine.

Antibiotics and antiseptics have been used to impregnate vascular catheters. The concern with the use of antibiotics has been that resistance might develop to antibiotics, preventing their use therapeutically and systemically in hospitalized patients. Furthermore, the durability of the existing antiseptics has been limited. For example, the use of chlorhexidine/silver sulfadiazine on polyurethane surfaces has had limited effectiveness. Moreover, chlorhexidine/silver sulfadiazine impregnating the surface of vascular catheters resulted in limited activity against gram-negative bacilli, such as Pseudomonas.

What is needed is a method of coating or impregnating medical devices with an antiseptic composition that will inhibit or prevent the nosocomial infections typically associated with the use of such medical devices. It would be desirable for such a method to produce devices with effective activity against infection, while avoiding destroying the devices or causing the devices to become toxic.

SUMMARY OF THE INVENTION

The present invention overcomes these and other drawbacks inherent in the art by providing novel methods for coating or impregnating medical devices such as catheters, tubes, stents, and sutures with antiseptic compositions in order to prevent the growth of pathogens in such devices and hence, to prevent infection to patients via such devices. The claimed methods achieve the desired activity against infection related to the use of the devices, while avoiding destroying the devices or causing the devices to become toxic. In addition, the invention provides medical devices coated or impregnated with antiseptic compositions by the aforementioned novel methods.

Therefore, in accordance with the present invention, there are provided methods for coating or impregnating a medical device with an antiseptic composition comprising (a) contacting the medical device for no more than about 10 minutes with a solvent comprising a basic reagent and a dye; and (b) drying the device. The method may further comprise the step of washing off excessive solvent from the medical device. In a particular embodiment, the method comprises contacting the medical device with the solvent by dipping and instantly withdrawing the device from the solvent. Other embodiments involve contacting the medical device with the solvent for no more than about 1, 2, 3, 4 or 5 minutes. In other embodiments, the medical device is immersed in the solvent or sprayed with the solvent. In some embodiments, the solvent contacted with the device can be methylene chloride, methanol, or a combination thereof.

In certain embodiments, the basic reagent may be bonded to the dye. In one aspect, the basic reagent and the dye are bonded ionically to form the antiseptic composition. In another aspect, the basic reagent and the dye are bonded covalently to form the antiseptic composition. The basic reagent and the dye can be combined in any amount to obtain the antiseptic composition of the invention, however, in a particular embodiment, an equimolar amount of the basic reagent is added to the dye solution. The inventors also contemplate that the antiseptic composition of the invention can be made by combining other amounts of the dye and basic reagent for example, one may combine, in molar ratios, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, 1:55, 1:60, 1:65, 1:70, 1:75, 1:80, 1.85, 1:90, 1:95, to 1:99 of either dye: basic reagent or basic reagent:dye. This includes all the intermediate ranges as well, for example it includes molar ratios such as, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1 and the like for other values listed. It also includes the ranges in between these values such as 1.11:1, 1.12:1 and so on. The skilled artisan will therefore recognize that the dye and basic reagent can be combined in different molar ratio amounts to obtain the antiseptic composition disclosed and that the invention is therefore not limited to any particular molar ratio of dye:basic reagent or basic reagent:dye.

In certain embodiments, the dye can be a triarylmethane dye, a monoazo dye, a diazo dye, an indigoid dye, a xanthene or a fluorescein dye, an anthraquinone dye, or a quinoline dye. In other specific embodiments, the dye is gentian violet, or crystal violet, ethyl violet, brilliant green, an FD&C dye, or a D&C dye. In one example, the FD&C dye is Blue No. 1 or Green No. 3. In another example, the triarylmethane dye is gentian violet. In yet another example, the monoazo dye is FD&C Yellow No. 5 or FD&C Yellow No. 6. In still another example, the diazo dye is D&C Red No. 17. The indigoid dye, may preferably be FD&C Blue No. 2. An example of a xanthene dye is FD&C Red No. 3, an example of an anthraquinone dye is D&C Green No. 6, and an example of a quinoline dye is D&C Yellow No. 1. In addition, Table 1 provides a list of different dyes that may be used in this invention. One of skill in the art will recognize that these examples are non-limiting and that the antiseptic compounds and compositions of the present invention can be made using almost any dye.

A wide variety of basic reagents can be used to form the antiseptic composition. The basic reagents include any nucleophilic species which includes all electron donor species. Some of the basic reagents that can be used include EDTA, a guanidium compound, a biguanide, a bipyridine, a phenoxide antiseptic, an alkyl oxide, an aryl oxide, a thiol, an aliphatic amine, or an aromatic amine and halides such as F⁻, Br⁻ and I⁻. Some examples of guanidium compounds that may be used include chlorhexidine, alexidine, and hexamidine. One example of a bipyridine compound that can be used to synthesize the antiseptics of the invention is octenidine. Examples of phenoxide antiseptics used include colofoctol, chloroxylenol, and triclosan.

In some particular embodiments, the antiseptic compound comprises compositions such as gendine, genlenol, genlosan, or genfoctol.

In one embodiment, the medical device contacted with the antiseptic composition is composed of latex. In another embodiment, the medical device is composed of latex silicone. In yet another embodiment, the medical device is composed of silicone. In still another embodiment, the medical device is composed of polyvinyl chloride or polyurethane.

The invention further provides medical devices coated or impregnated with an antiseptic composition by a process comprising (a) contacting the medical device for no more than about 10 minutes with a solvent comprising a basic reagent and a dye; and (b) drying the device. The method may further comprise the step of washing off excessive solvent from the medical device. Specific embodiment involves contacting the medical device with the solvent and immediately withdrawing the device from the solvent. Other embodiments involve contacting the medical device with the solvent for no more than about 1, 2, 3, 4 or 5 minutes. In other embodiments, the medical device is immersed in the solvent or sprayed with the solvent. In some embodiments, the solvent contacted with the device can be methylene chloride, methanol, or a combination thereof.

The invention also provides medical devices wherein the basic reagent and the dye in the solvent are bonded. In one aspect, the medical devices are contacted with a basic reagent and a dye that are ionically bound. In another aspect, the medical devices are contacted with a basic reagent and a dye that are covalently bound.

In one embodiment, the medical device may be composed of latex. In another embodiment, the medical devices is composed of latex silicone. In yet another embodiment, the medical device is composed of silicone. In still another embodiment, the medical device is composed of polyvinyl chloride, polyurethane or any other material from which medical devices, prostheses or grafts are made.

Examples of medical devices include a tracheostomy tube, a nasogastric tube, an endotracheal tube, a percutaneous gastric tube, a percutaneous jejunostomy tube, a nasojejunal tube, a vascular catheter, a urinary catheter, a nephrostomy tube, a biliary stent, a peritoneal catheter, an epidural catheter, a central nervous system catheter, an orthopedic device, a prosthetic valve, and a medical implant. The vascular catheter may be a central venous catheter, an arterial line, an pulmonary artery catheter, and a peripheral venous catheter. The central nervous system catheter may be an intraventricular shunt. Other medical devices that can benefit from the present invention include blood exchanging devices, vascular access ports, cardiovascular catheters, extracorpeal circuits, stents, implantable prostheses, vascular grafts, pumps, heart valves, and cardiovascular sutures, to name a few. Regardless of detailed embodiments, applicability of the invention should not be considered limited with respect to the type of medical device, implant location or materials of construction of the device.

As used herein the specification and claim(s), the words “a” or “an” when used in conjunction with the word “comprising” may mean one or more. As used herein the specification and claim(s), the words “ionic bonding” or “ionically bound” refers to the electrostatic interactions among ions which can be formed by the transfer of one or more electrons from one atom or group of atoms to another, to create an ionic bond between the basic reagent and the dye comprising an antiseptic compound.

As used herein the specification and claim(s), the words “covalent bonding” or “covalently bound” refers to the chemical bond formed by the sharing of one or more pairs of electrons between the basic reagent and the dye comprising an antiseptic compound. As used herein the specification and claim(s), the word “about” when used in reference to time means within 10 seconds.

Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

FIG. 1—Efficacy and Durability of Gendine-Coated Urinary Catheter (GND-UC). GND-UC produced a baseline ZOI of 23 mm against Candida albicans (CA), 20 mm against vancomycin resistant enterococci (VRE) and 18 mm against E. coli (EC).

FIG. 2—Efficacy and Durability of Gendine-Coated Endotracheal Tubes (GND-ETT). GND-ETT produced a baseline ZOI of 32 mm against Candida prapsilosis (CP), 28 mm against methicillin resistant S. aureus (MRSA) and 26 mm against E. coli (EC).

FIG. 3—Bacterial Adherence to Urinary Catheters. There was a significant reduction (P=0.001) in the number of colonies of methicillin resistant S. aureus (MRSA), Candida prapsilosis (CP), and E. coli (EC) adhering to gendine-coated segments in comparison to control uncoated segments and silver hydrogel UC.

FIG. 4—Bacterial Adherence to Endotracheal Tubes (ETT). There was significant reduction in the number of CFU isolated from the surface of GND-ETT in comparison to control uncoated ETT (P=0.003 for methicillin resistant S. aureus (MRSA), Candida prapsilosis (CP), and E. coli (EC); P=0.023 for Pseudomonas aeruginosa (PS).

FIGS. 5A-D—Effects of Solvents on Various Devices. (FIG. 5A) Central Venous Catheter—Polyurethane; (FIG. 5B) Chest Tube—PVC; (FIG. 5C) Nasal-jejunal tubes—PVC; (FIG. 5D) Endotracheal Tube—PVC.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Most nosocomial infections are caused by the contamination of medical devices resulting in serious hospital-acquired infections. The present invention provides methods of coating or impregnating medical devices with an antiseptic composition that will inhibit or prevent the nosocomial infections typically associated with the use of such medical devices. However, devices contacted with antiseptic compositions for too long can be destroyed or become toxic, while devices contacted with antiseptic compositions too briefly can fail to obtain the desired activity against infection. Therefore, the present invention further provides methods of coating or impregnating medical devices that produce devices with effective activity against infection, while avoiding destroying the devices or causing the devices to become toxic. In addition, the invention provides medical devices coated or impregnated with antiseptic compositions by the aforementioned novel methods.

A. The Present Invention

Indwelling catheters and other similar implanted medical devices are used routinely in hospitals on a diverse group of patients. A common cause of failure of these medical devices is infection. Pathogens often attach to and proliferate in such devices and eventually invade the patient leading to nosocomial infections. Microorganisms usually migrate along the surfaces of devices to invade sterile environments, such as the bronchoalveolar space leading to pneumonia, the bloodstream leading to bacteremia, or the urinary bladder leading to urinary tract infections.

In U.S. patent application Ser. No. 10/044,842 (Publication No. US-2003-0078242-A1), which is incorporated herein by reference, Applicants disclosed methods of coating or impregnating medical devices with antiseptic compositions with broad-spectrum activity against various nosocomial microorganisms, including resistant bacteria and fungi. For example, the antiseptic compositions disclosed in that application are effective against resistant staphylococci, vancomycin-resistant enterococci, resistant Pseudomonas aeruginosa and Candida species. These antiseptics also have unique properties that enable penetration/impregnation of various polymers, such as polyvinyl chloride, polyethylene, silastic elastomers, polytetrafluoroethylene, dacron, collodion, carboethane, nylon, polymers used in the formation of endotracheal tubes, silicone and polyurethane polymers used in the formation of vascular catheters and surgical silk sutures.

The inventors demonstrated that these antiseptics may maintain prolonged antimicrobial activity on device surfaces, and thus may be used for the entire lifespan of these indwelling devices. This is an improvement over existing coated or impregnated devices where the antimicrobial activity of the device diminishes over time and eventually disappears altogether. For example, several prior art patents and publications describe methods of coating which generated medical devices wherein the effectiveness of the coating diminishes over time. After insertion of the medical device, the antibiotics and/or antiseptics quickly leach from the surface of the device into the surrounding environment. Over a relatively short period of time, the amount of antibiotics and/or antiseptics present on the surface decreases to a point where the protection against bacterial and fungal organisms is no longer effective. Thus, the present invention provides safe antiseptic treated devices wherein the antiseptic coating has a durability that may last through the life-span of the device. This significantly decreases patient mortality and morbidity associated with the various nosocomial infections such as nosocomial pneumonias, nosocomial bacteremias, nosocomial urinary tract infections and nosocomial surgical wound infections. For example, creation of antiseptic-impregnated/coated catheters prevents organisms from adhering to or migrating on catheter surfaces. Thus, when a pathogenic organism approaches the catheter surface, it is killed by the antiseptics.

The present invention provides a further improvement on these methodologies by defining a specific period of time for immersion of devices that are made of labile compositions. By limiting the exposure time to the solvent, the toxicity associated with composition breakdown, and the break down itself is avoided.

The methods disclosed in the present invention incorporate broad-spectrum antiseptic derivatives. The general method for synthesis of the antiseptic derivatives involves the binding of a dye with one or more basic reagents. Different types of dyes and basic reagents can be used to prepare the antiseptic compounds of this invention.

The dyes that may be used to synthesize the antiseptic compounds of the invention include but are not limited to, gentian, or crystal violet, ethyl violet, brilliant green, etc., and the FD&C dyes such as Blue No. 1 and Green No. 3. In addition, other dyes include the following FD&C and D&C colors: (1) Monoazo dyes such as, but not limited to, FD&C Yellow No. 5, FD&C Yellow No. 6, (2) Diazo dyes such as, but not limited to, D&C Red No. 17, (3) Indigoid dyes such as, but not limited to, FD&C Blue No. 2, (4) Xanthene (Fluorescein) dyes such as, but not limited to, FD&C Red No. 3, (5) Anthraquinone dyes such as, but not limited to, D&C Green No. 6, (6) Quinoline dyes such as, but not limited to, D&C Yellow No. 1. An extensive list of dyes and stains that may be employed is also provided in Table 1.

The basic reagents can be alkyl and aryl oxides, thiols, sulfides, phosphorous, aliphatic and aromatic amines, guanidines and halides such as F⁻, Br⁻ and I⁻. Some examples of the basic reagents that can be used include phenoxide antiseptics (such as clofoctol, chloroxylenol, triclosan) or guanidium compounds (such as chlorhexidine, alexidine, hexamidine), bipyridines (such as octenidines), EDTA or other chelators. TABLE 1 The Color Index (C.I.) Number and/or Chemical Abstracts Service Registry CAS) Number for Dyes and Stains that may be Employed to Stain Medical Devices No. C.I. # CAS # 1 15670 2092-55-9 2 26370 3071-73-6 3 20460 5850-35-1 4 62130 2666-17-3 5 61585 4474-24-2 6 26360 3351-05-1 7 62058 6397-02-0 8 42685 3244-88-0 9 61580 6408-57-7 10 15575 5850-86-2 11 22870 15792-50-4 12 18050 3734-67-6 13 14900 4787-93-3 14 18070 12167-45-2 15 22890 10169-02-5 16 23635 6459-94-5 17 18800 6408-31-7 18 18055 4321-69-1 19 18965 6359-98-4 20 18900 6359-91-7 21 25135 13390-47-1 22 22910 6375-5-9 23 18850 6359-88-2 24 46005:1 494-38-2 25 8048-52-0 26 58000 72-48-0 27 3952-78-1 28 61710 6408-63-5 29 42750 30586-13-1 30 569-58-4 31 52417-22-8 32 520-10-5 33 48035 3056-93-7 34 4431-00-9 35 50090 25360-72-9 36 52010 531-55-5 37 61111 12217-43-5 38 42500 569-61-9 39 11460 42373-04-6 40 23500 992-59-6 41 298-95-3 42 21010 5421-66-9 43 1871-22-3 44 28440 2519-30-4 45 42660 6104-59-2 46 27290 5413-75-2 47 24890 3051-11-4 48 76-60-8 49 115-40-2 50 115-39-9 51 65005 1328-24-1 52 62055 6408-78-2 53 62125 6424-85-7 54 63010 2861-02-1 55 13390 3861-73-2 56 26400 3529-01-9 57 15706 12392-64-2 58 61570 4403-90-1 59 62560 4430-16-4 60 26550 8003-88-1 61 18745 10127-27-2 62 14710 5858-39-9 63 17045 6360-07-2 64 15620 1658-56-6 65 18110 6844-74-2 66 26900 6406-56-0 67 18125 10130-48-0 68 42650 4129-84-4 69 18835 6359-85-9 70 18890 6359-90-6 71 18950 6372-96-9 72 14170 6408-90-8 73 13900 10343-58-5 74 46025 135-49-9 75 12840 61968-76-1 76 63615 1324-21-6 77 58005 130-22-3 78 14025 584-42-9 79 42080 3486-30-4 80 16185 915-67-3 81 42780 82 1668-00-4 83 41000 2465-27-2 84 43810 13186-45-3 85 52005 531-53-3 86 51004 33203-82-6 87 11075 94233-04-2 88 42510 632-99-5 89 48055 4208-80-4 90 26905 4196-99-0 91 2315-97-1 92 21000 10114-58-6 93 16180 5858-33-3 94 42655 6104-58-1 95 81029-05-2 96 42040 633-03-4 97 102185-52-4 98 62625-32-5 99 62625-30-3 100 62625-28-9 101 14337-53-2 102 76-59-5 103 40070-59-5 104 3147-14-6 105 24410 2610-05-1 106 43825 1667-99-8 107 16575 548-80-1 108 43820 3564-18-9 109 24895 2870-32-8 110 18972 50662-99-2 111 596-27-0 112 2303-01-7 113 1733-12-6 114 10510-54-0 115 15970 1934-20-9 116 15391-59-0 117 76-54-0 118 4727-50-8 119 54-88-6 120 6473-13-8 121 23655 6420-03-7 122 25380 2829-43-8 123 27905 5489-77-0 124 13950 10190-68-8 125 29025 3214-47-9 126 64500 2475-45-8 127 61500 2475-44-7 128  1005 730-40-5 129 31482-56-1 130 11115 3180-81-2 131 11855 2832-40-8 132 26090 6300-37-4 133 45400 548-24-3 134 45380 548-26-5 135 15086-94-9 136 14640 3564-14-5 137 42090 3844-45-9 138 45430:2 15905-32-5 139 45386 6359-05-3 140 76058-33-8 141 23860 314-13-6 142 11160 97-56-3 143 13015 2706-28-7 144 11285 6416-57-5 145 45350:1 2321-07-5 146 596-09-8 147 3326-34-9 148 51030 1562-85-2 149 1634-82-8 150 3737-95-9 151 165660-27-5 152 16574-43-9 153 34722-90-2 154 617-19-6 155 51050 1562-90-9 156 4430-20-0 157 14720 3567-69-9 158 16570 4197-07-3 159 11270 532-82-1 160 18105 17681-50-4 161 22120 573-58-0 162 2411-89-4 163 62625-31-4 164 62625-29-0 165 41830-80-2 166 42555 548-62-9 167 45370:1 596-03-2 168 620-45-1 169 45425:1 31395-16-1 170 73688-85-4 171 34140 4399-55-7 172 29160 3441-14-3 173 28160 2610-11-9 174 13920 10130-29-7 175 19556 6537-66-2 176 36900 6409-90-1 177 61505 2475-46-9 178 11080 2581-69-3 179 26080 6253-10-7 180 11110 2872-52-8 181 11130 2734-52-3 182 12790 6439-53-8 183 518-82-1 184 56360-46-4 185 45380:2 15086-94-9 186 14645 1787-61-7 187 18760 3618-63-1 188 45430 568-63-8 189 1239-45-8 190 62758-12-7 191 42600 2390-59-2 192 37190 64071-86-9 193 42053 2353-45-9 194 12010 6535-42-8 195 18820 6359-82-6 196 45350 518-47-8 197 3326-32-7 198 51649-83-3 199 42085 4680-78-8 200 75290 517-28-2 201 90-33-5 202 73000 482-89-3 203 73015 860-22-0 204 12210 4569-88-4 205 11050 2869-83-2 206 44090 3087-16-9 207 42000 2437-29-8 208 13065 587-98-4 209 52041 2516-05-4 210 45385 23391-49-3 211 13025 547-58-0 212 32469-43-5 213 14855 3624-68-8 214 11335 6247-27-4 215 11880 6370-46-3 216 11300 6232-53-7 217 26520 3564-27-0 218 18735 1934-24-3 219 14010 6054-99-5 220 44530 5715-76-4 221 11350 131-22-6 222 16255 2611-82-7 223 52030 6586-05-6 224 7385-67-3 225 74-39-5 226 60760 6409-77-4 227 26120 4477-79-6 228 16230 1936-15-8 229 15705 2538-85-4 230 19010 10127-05-6 231 42045 129-17-9 232 34487-61-1 233 101-75-7 234 11800 1689-82-3 235 45410 18472-87-2 236 16680 1058-92-0 237 27190 6226-78-4 238 49000 30113-37-2 239 16593-81-0 240 85531-30-2 241 45005 92-32-0 242 58500 81-61-8 243 47000 8003-22-3 244 20505 17095-24-8 245 61205 13324-20-4 246 17908 25489-36-5 247 635-78-9 248 45170 81-88-9 249 45160 989-38-8 250 45440 632-69-9 251 50240 477-73-6 252 61552 6994-46-3 253 7423-31-6 254 3599-32-4 255 146-68-9 256 42095 5141-20-8 257 42000:1 510-13-4 258 129-16-8 259 52015 61-73-4 260 50206 4569-86-2 261 42590 7114-03-6 262 13020 493-52-7 263 11020 60-11-7 264 20110 3564-15-6 265 11875 6247-28-5 266 13250 3618-62-0 267 14030 2243-76-7 268 26560 6406-37-7 269 6408-91-9 270 14045 6470-98-0 271 20470 1064-48-8 272 50040 553-24-2 273 42520 3248-91-7 274 51180 3625-57-8 275 14890 5423-07-4 276 56431-61-9 277 61555 2646-15-3 278 26125 1320-06-5 279 15510 633-96-5 280 15711 5610-64-0 281 12070 6410-10-2 282 143-74-8 283 11000 60-09-3 284 16201-96-0 285 975-17-7 286 2768-90-3 287 27195 6226-79-5 288 67627-18-3 289 58205 (75410) 81-54-9 290 115-41-3 291 45010 2150-48-3 292 117-92-0 293 58050 81-64-1 294 47005 8004-92-0 295 61211 12236-82-7 296 17757 12225-82-1 297 61200 2580-78-1 298 123333-76-6 299 45170:1 509-34-2 300 13161-28-9 301 43800 603-45-2 302 61554 17354-14-2 303 61565 128-80-3 304 12055 842-07-9 305 12140 3118-97-6 306 26105 85-83-6 307 11920 2051-85-6 308 123359-42-2 309 23647-14-5 310 45100 3520-42-1 311 19140 1934-21-0 312 108321-10-4 313 62637-91-6 314 6262-21-1 315 632-73-5 316 42798-98-1 317 19540 1829-00-1 318 52000 78338-22-4 319 81012-93-3 320 123359-43-3 321 12120 2425-85-6 322 23850 72-57-1 323 44045 2580-56-5 324 42595 2390-60-5 325 125-31-5 326 16150 3761-53-3 327 135-52-4 328 26100 85-86-9 329 26150 4197-25-5 330 26050 6368-72-5 331 68504-35-8 332 123333-78-8 333 45220 5873-16-5 334 4430-25-5 335 1301-20-8 336 123333-63-1 337 386-17-4 338 4430-24-4 339 1719-71-7 340 49005 2390-54-7 341 76-61-9 342 125-20-2 343 52040 92-31-9 344 14270 547-57-9 345 14541-90-3 346 44040 2185-86-6 347 45190 6252-76-2 348 63721-83-5 349 14936-97-1 350

One unique feature of these antiseptics is that they do not require another vehicle to attach to a surface. The adhesive potential of the dye makes them self-adhesive to surfaces of devices.

The antiseptic compound is applied on the surface of a device by simply contacting the device with the antiseptic solution, air drying, and optionally washing off excessive solvent. The self-impregnating property of the dyes such as for example, the triarylmethane dyes, removes the need for another binding agent. This is another feature of the compositions utilized by this invention which is a considerable improvement over other known compositions. Previously known compositions require other impregnating/coating agents and/or must typically be extruded into the device as it is made. Both these methods are time consuming and involve additional steps and techniques. For example, one method of coating devices first requires application or absorbtion of a layer of surfactant, such as tridodecylmethyl ammonium chloride (TDMAC) followed by the antibiotic coating layer, to the surface of the medical device. Another method used to coat surfaces of medical devices with antibiotics involves first coating the selected surfaces with benzalkonium chloride followed by ionic bonding of the antibiotic composition (Solomon and Sherertz, 1987; U.S. Pat. No. 4,442,133). Other methods of coating surfaces of medical devices with antibiotics are taught in U.S. Pat. No. 4,895,566 (a medical device substrate carrying a negatively charged group having a pH of less than 6 and a cationic antibiotic bound to the negatively charged group); U.S. Pat. No. 4,917,686 (antibiotics are dissolved in a swelling agent which is absorbed into the matrix of the surface material of the medical device); U.S. Pat. No. 4,107,121 (constructing the medical device with ionogenic hydrogels, which thereafter absorb or ionically bind antibiotics); U.S. Pat. No. 5,013,306 (laminating an antibiotic to a polymeric surface layer of a medical device); and U.S. Pat. No. 4,952,419 (applying a film of silicone oil to the surface of an implant and then contacting the silicone film bearing surface with antibiotic powders). Furthermore, most of the methods previously employed to coat the surfaces of medical devices use antibiotics such as tetracyclines, penicillins, cephalosporins and the beta-lactam antibiotics. The main drawback with antibiotics is the emergence of resistant strains.

Thus, the invention utilizes antiseptic derivative compounds with broad-spectrum antiseptic activity against bacteria and fungi including nosocomial and multidrug-resistant varieties with the additional ability to impregnate, bind, coat, adhere and/or attach to various device surfaces without the assistance of impregnating vehicles such as tridodecylmethylammonium chloride (TDMAC). Furthermore, the antiseptic compounds of the invention also have an extended antimicrobial efficacy that can cover the life of the device.

One example of the broad-spectrum antiseptic derivatives of this invention is gendine, which consists of the combination of gentian violet and chlorhexidine. Gentian violet, on its own, is a good impregnating triarylmethane dye. Bhatnager et al., 1993 have shown in an in vitro study that gentian violet alone can be used to impregnate the surface of CSF silicone shunts and prevent the colonization of S. epidermis on these surfaces. However, after impregnating the surfaces of various polymers, including polyvinylchloride, gentian violet on its own has no activity against Pseudomonas aeruginosa, which is the second most common cause of nosocomial pneumonia and the third most common cause of nosocomial urinary tract infections. Antiseptics such as chlorhexidine cannot attach well on their own onto the surfaces of polyvinylchloride tubes or silicone catheters and silk sutures. They require an impregnating vehicle. Furthermore, on their own they are not highly active against Pseudomonas aeruginosa. On the other hand, upon combining gentian violet with chlorhexidine, the new antiseptic agent synthesized, is a potent and effective broad-spectrum antiseptic and has the additional ability to coat/impregnate various device surfaces. Gendine is unique in its ability to impregnate various device polymers, such as polyvinylchloride used in the formation of endotracheal tubes, silicone and polyurethane polymers used in the formation of vascular, as well as peritoneal, epidural, urinary and intraventricular catheters. In addition, gendine is able to impregnate the silk sutures used in surgical wounds.

In addition to Gendine, other antiseptics utilized by this invention are Genlenol and Genfoctol.

In coating or impregnating medical devices with antiseptic compositions, a problem arises when the devices are contacted with the compositions for an improper amount of time. If the devices are contacted with the compositions for too long, the devices can become toxic. In addition, contacting the devices with the compositions for too long can lead to destruction of the devices. Applicants have now discovered that contacting the medical devices with the antiseptic compositions for a limited amount of time produces the surprising and unexpected results of (a) no destruction, (b) and no toxicity in, and (c) adequate coating. Immersion and spraying are both effective means of contacting the medical devices with the antiseptic compositions.

The invention also provides methods to generate antiseptic medical devices composed of a wide variety of materials. Some examples of those materials include latex, latex silicone, silicone, and polyvinyl chloride. In addition, the invention provides a wide variety of antiseptic medical devices. Some examples include antiseptic endotracheal tubes, antiseptic vascular catheters, including central venous catheters, arterial lines, pulmonary artery catheters, and peripheral venous catheters, antiseptic urinary catheters, antiseptic nephrostomy tubes, antiseptic stents such as biliary stents, antiseptic peritoneal catheters, antiseptic epidural catheters, antiseptic naso-gastric and nasojejunal tubes, antiseptic central nervous system catheters, including intraventricular shunts and devices, antiseptic prosthetic valves, and antiseptic medical implants.

B. Pathogens

The nosocomial bacterial infections result in diseases such as bacteremia, pneumonia, meningitis, osteomyelitis, endocarditis, sinusitis, arthritis, urinary tract infections, tetanus, gangrene, colitis, acute gastroenteritis, bronchitis, and a variety of abscesses, and opportunistic infections. Bacterial pathogens include Gram-positive cocci such as Staphylococcus aureus, coagulase negative staphylocci such as Staphylococcus epidermis, Streptococcus pyogenes (group A), Streptococcus spp. (viridans group), Streptococcus agalactiae (group B), S. bovis, Streptococcus (anaerobic species), Streptococcus pneumoniae, and Enterococcus spp.; Gram-negative cocci such as Neisseria gonorrhoeae, Neisseria meningitidis, and Branhamella catarrhalis; Gram-positive bacilli such as Bacillus anthracis, Corynebacterium diphtheriae and Corynebacterium species which are diptheroids (aerobic and anerobic), Listeria monocytogenes, Clostridium tetani, Clostridium difficile, Escherichia coli, Enterobacter species, Proteus mirablis and other spp., Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella, Shigella, Serratia, and Campylobacter jejuni. The antibiotic resistant bacteria that can be killed by the antiseptic coated devices of the present invention include Staphylococci (methicillin-resistant strains), vancomycin-resistant enterococci (Enterococcus faecium), and resistant Pseudomonas aeruginosa.

Fungal infections that may be prevented include fugal infections (mycoses), which may be cutaneous, subcutaneous, or systemic. Superficial mycoses include tinea capitis, tinea corporis, tinea pedis, onychomycosis, perionychomycosis, pityriasis versicolor, oral thrush, and other candidoses such as vaginal, respiratory tract, biliary, eosophageal, and urinary tract candidoses. Systemic mycoses include systemic and mucocutaneous candidosis, cryptococcosis, aspergillosis, mucormycosis (phycomycosis), paracoccidioidomycosis, North American blastomycosis, histoplasmosis, coccidioidomycosis, and sporotrichosis. Fungal infections include opportunistic fungal infections, particularly in immunocompromised patients such as those with AIDS. Fungal infections contribute to meningitis and pulmonary or respiratory tract diseases.

Other pathogenic organisms that may be prevented from causing the infections include dermatophytes (Microsporum canis and other M spp.; and Trichophyton spp. such as T. rubrum, and T. mentagrophytes), yeasts (e.g., Candida albicans, C. Parapsilosis, C. glabrata, C. Tropicalis, or other Candida species including drug resistant Candida species), Torulopsis glabrata, Epidermophytonfloccosum, Malassezia fuurfur (Pityropsporon orbiculare, or P. ovale), Cryptococcus neoformans, Aspergillus fumigatus, and other Aspergillus spp., Zygomycetes (Rhizopus, Mucor), hyalohyphomycosis (Fusarium Spp.), Paracoccidioides brasiliensis, Blastomyces dermatitides, Histoplasma capsulatum, Coccidioides immitis, and Sporothrix schenckii. Fungal infections include Cladosporium cucumerinum, Epidermophyton floccosum, and Microspermum ypseum.

C. EXAMPLES

The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.

Example 1 Synthesis of Gendine and Impregnation of Devices

Impregnation Procedure. The general procedure involves, and when applicable, prior preparation of the basic reagent (such as chlorhexidine) in anhydrous solvent, addition of the basic reagent to a solution of a dye (such as Gentian violet) in anhydrous solvent (or addition of the dye to the basic solution), stirring the resulting mixture for 30-90 minutes at ambient conditions, evaporating the solvent also under ambient conditions, and finally dissolution of the residue prior to impregnation. The following procedure illustrates impregnation with Gendine, an example for employing a basic guanidium derivative (e.g., chlorhexidine) and triarylmethane dye (e.g., Gentian violet).

Potassium tert-butoxide in THF, 7.35 ml of 1M solution, was added to a solution of CHX diacetate, 1.533 g; 2.45 mmol in 35 ml THF. The resulting heterogeneous solution was stirred for 20 minutes, then added to a solution GV, 1.0 g; 2.45 mmol, in 30 ml THF (GV used as an example of Triarylmethane Dye). The mixture was stirred at ambient conditions for 1 hour, then placed under the hood overnight to evaporate the solvent. The resulting residue was dissolved in 30 ml DCM (or MeOH). When applicable, the base (such as neutral form of chlorhexidine) is added to a stirring solution of dye (such as GV) in DCM and the resulting mixture is stirred for at least 1 h. With anionic dyes, dissolution is achieved with the addition of at least one equivalent of a quaternary amine (such as tetraethylammonium) prior to addition of the base. One-centimeter device segments were immersed in the solution for the appropriate period, generally PVC and PU were dipped and instantly removed; silicone (Si) and silk suture for 2 hours. The devices were removed from the solution, and traces of solution were removed from the lumen when applicable. The impregnated devices were placed under the hood to dry for at least 4 hours, preferably over night, then washed with distilled water until the washings were colorless or very faint, and finally placed under an aseptic hood to dry under ambient conditions for at least 4 hours, preferably overnight.

In Vitro antimicrobial activity. The antimicrobial activity of impregnated catheters was evaluated in duplicate by a modified Kirby-Bauer technique. BBL Mueller Hinton II agar plates (obtained from Fisher Scientific) were inoculated with 0.5 McFarland of the appropriate microorganism (hospital isolates from the MD Anderson Cancer Center). Then 10 mm segments of impregnated devices were embedded in the inoculated plates and placed in an incubator at about 37° C. for at least 18 hours. Zones of inhibition were measured perpendicular to the long axis of the device.

Results and Discussion. Tables 2 and 3 illustrate zones of inhibition obtained for Gendine-impregnated devices. TABLE 2 Urinary Catheters - “Instantly Dip” Baseline 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week EC 3364 18:18 17:16 15:15 16:15 16:16 16:15 13:13 14:13 12:11 CA 145-0951 24:23 22:22 20:20 19:18 19:19 18:18 18:18 16:15 15:15 VRE 22:20 18:18 18:18 17:17 17:16 13:13 13:12 13:13 12:11 EC = E. coli CA = Candida albicans VRE = Vancomycin resistant enterococci

TABLE 3 Endotracheal PVC Tubes Week Week Week Organism Baseline Week 1 Week 2 Week 3 4 5 6 Non-rewashed ETT pieces: MRSA 32, 32 27, 27 28, 26 24, 23 PS 25, 23 22, 21 18, 17 18, 18 CP 34, 34 30, 30 26, 24 24 VRE 28, 28 26, 25 22, 22 21 Re-washed ETT pieces: MRSA 30, 30 27, 26 27, 27 27 CP 34, 34 28, 26 28, 27 stopped PS 18, 18 MRSA = Methicillin resistant Staph. aureus PS = Pseudomonas aeruginosa CP = Candida parapsilosis VRE = Vancomycin resistant enterococci

In addition to the simplicity of the impregnation procedure, and the availability of the requisite reagents, one unique feature of gendine-impregnated devices is its broad spectrum activity, not only against the worldwide problematic gram-positive MRSA, which has increased in frequency at an alarming rate as a cause of device-related infections, but also against Pseudomonas aeruginosa, an increasingly prevalent opportunistic human pathogen, and the most common gram-negative bacterium found in nosocomial infections. They are intrinsically more resistant than gram-positive bacteria to many antiseptics, particularly when present in a biofilm or when associated with a device infection (Platt et al., 1988). This is important especially since Pseudomonas aeruginosa is responsible for 16% of nosocomial pneumonia cases (and is considered by the Centers for Disease Control as the second most common cause of nosocomial ventilator associated pneumonia), 12% of nosocomial urinary tract infections, 8% of surgical wound infections, and 10% of nosocomial bloodstream infections (Van Delden and Iglewski, 1998).

Staphylococcal resistance to antiseptics are known worldwide (Russell, 1997). In addition to CHX, low-level resistance to three antiseptics (acriflavin, benzalkonium chloride, and hexamidine diisethionate is documented (Reverdy et al., 1992; Townsend et al., 1985; Heir et al., 1995). The present study reveals that all GN-impregnated devices tested, exhibit significant biocidal activity against methicillin-resistant staphylococci. This finding is extremely important in light of the fact that methicillin-resistant staphylococci (MRSA and MRSE) are the leading causes of device-related infections, including vascular catheter-related bacteremia and surgical wound infections. In addition S. aureus is one of the leading causes of nosocomial pneumonia (Klempner et al., 1998).

The effectiveness of gendine-impregnated devices against Candida is no less noteworthy. As revealed from the results presented here, devices impregnated with GN exhibit fair to good activity against Candida. Catheter-related candidemia is now the third leading cause of vascular catheter-related bloodstream infections (Raad et al., 1992). In addition, candidemia in severely immunocompromised patients (i.e., HIV, bone-marrow recipients and leukemia patients) is an important cause for morbidity and mortality and catheters are a major source for this infection (Tumbarello et al., 1998; Gonzalez et al., 1996; Lecciones et al., 1992; Wey et al., 1989). The known chlorhexidine-sulfadiazine impregnated catheters and the minocycline-rifampin impregnated catheters do not have significant prophylactic effect against fungi (Tacconelli et al., 1997; Raad et al., 1997).

Other GV preparations. Antiseptics chloroxylenol [p-chloro-m-xylenol; 4-chloro-3,5-dimethylxylenol (PCMX)], Clofoctol [α-2,4-dichlorophenly)-4-(1,1,3,3-tetramethylbutyl)-o-cresol (CFTL), and Triclosan [2,4,4′-trichloro-2′hydroxydiphenyl ether](TLS) are three of the phenolic antiseptic reagents included in this study. The first disinfectant is the first halophenol employed in many antiseptic and disinfectant formulations. Neither the neutral form of PCMX nor its sodium salt could produce in vitro zones of inhibition on their own through coating or impregnating the catheter devices and sutures. However, when the salt is reacted with GV (as an example of a triarylmethane dye), the resulting products (new products such as Genlenol, Genlosan and Genfoctol) are immobilized on the devices producing large in vitro zones of inhibition against various nosocomial pathogens. Meanwhile, Genlenol (GV⁺.PCMX⁻) not only increased the zone against MRSA considerably for the silicone catheter, but also produced a large zone against C. parapsilosis. Similar results were observed for silk sutures. Improvements in the zones of inhibition against C. parapsilosis are also observed for PVC tubes and PVC catheters, and to a large extent against Alcaligenes faecalis (a gram negative bacillary organism) for the PVC tubes. These results are summarized in Table 4. Similar trends were observed for Genfoctol (GV⁺. CFTL⁻), but with much larger zones for sutures against MRSA and C. parapsilosis. TABLE 4 Zones of Inhibition Imparted by Silk Sutures Zones of Inhibition (in mm) against Reagent MRSA₂₀₆₆ C. Parap.₁₋₁₀₀₋₀₀₂₂ GV^(♯) 8:8 0:0 PCMX^(♭) 0:0 0:0 GV⁺.PCMX^(−*) 11:11 5:5 CFTL^(═) 0:0 0:0 GV⁺.CFTL^(−π) 17:17 15:16 ^(♯)Gentian violet. ^(♭)Chloroxylenol. *Genlenol. ^(═)Clofoctol. ^(π)Genfoctol.

In general, many other gentian violet basic preparations significantly affect the efficacy and biocidal activity of coated sutures and silicone-impregnated catheters against MRSA and C. parapsilosis. Some examples are shown below in Table 5. TABLE 5 Zones of Inhibition Imparted by Silicone Catheters and Silk Sutures Zones of Inhibition (in mm) against MRSA₂₀₆₆ C. Parap.₁₋₁₀₀₋₀₀₂₂ Reagent Si-catheter Silk Suture Si-catheter Silk Suture GV^(♯) 6:7 8:8 0:0 0:0 GV⁺OH⁻ 18:19 17:17 19:19 13:14 GV^(♯)OCH₃ ⁻ 18:19 15:15 25:25 10:13 GV^(♯)Glycerin⁻ 19:20 13:14 18:18 9:9 GV^(♯)HEDTA^(−4♭) 13:13 7:7  9:13 4:5 GV^(♯)TCSA^(−═) 14:14 12:13 11:11 10:10 GV^(♯)MBT^(−π) 13:13 8:8 12:12 0:0 Gentian violet. ^(♭)Trisodium n-(2-Hydroxyethyl)ethylenediaminetriacetate. ^(═)TCSA = 3′,4′,5-Trichlorosialicyl-anilide. ^(π)MBT = 2-Mercaptobenzothiazole.

The above data clearly demonstrate significant improvement in the biocidal activity of impregnated or coated silicone catheters and silk sutures by the antiseptic derivatives of the invention.

Example 2 Clinical Trials

The antiseptic devices of the invention pose no significant risk. Hence, preclinical studies (animal studies) may not be required. This section is concerned with the development of human treatment protocols using the antiseptic medical devices of the present invention.

The various elements of conducting a clinical trial, including patient treatment and monitoring, will be known to those of skill in the art in light of the present disclosure. The following information is being presented as a general guideline for use in establishing the use of the antiseptic medical devices.

Candidates will be patients who are seriously ill and are required to use a medical device such as those described in the sections above. The medical devices in these cases will be treated with Gendine, Genelol, Genfoctol, Genlosan or other antiseptic derivatives that can be synthesized by the methods provided herein, and the patients will be monitored for the occurrence of nosocomial infections.

To monitor the development of infections and to evaluate the efficacy of the antiseptic coated/impregnated medical devices in preventing the spread of infectious agents through the devices it is contemplated that the patients will be examined for appropriate tests every month. Tests that will be used to monitor the effectiveness of the treated medical device include: physical exam, X-ray, blood work and other clinical laboratory methodologies used to detect pathogens in the patients and also methods to detect presence of pathogens in the medical device. Described below is a study guideline for patients using central venous catheters.

Patient Eligibility. Patients will be recruited from intensive care units, bone marrow transplant and melanoma services and other hospital divisions where catheters are used routinely on inpatients. Patients who require a new insertion of a central venous catheter (CVC) and have none of the exclusion criteria will be approached to obtain informed consent. The exclusion criteria are the following:

-   -   1. Age <18 years     -   2. Dermatitis over catheter insertion site     -   3. Pregnancy     -   4. Allergy to chlorhexidine or gentian violet     -   5. Expected duration of catheter placement <3 days     -   6. Inability to obtain informed consent         The eligible consenting patient will be informed that the         catheter to be inserted has either been coated with an         antiseptic compound (for example Gendine) or has not been         coated, but the subject will not be informed as to whether the         specific catheter to be inserted contains the compound.

Each female with child bearing potential will have a urine sample prior to catheter placement to test for pregnancy (if appropriate).

Catheter insertion. Catheters will be inserted into a subclavian vein or internal jugular vein using gown, mask, sterile gloves and full sterile drapes. Skin will be prepped using povidone iodine allowing 1 minute of exposure time. After insertion, the catheter will be secured to the skin using tape and the skin puncture site will be covered with povidone-iodine ointment. Then, the insertion site and the surrounding area will be covered with sterile gauze and taped securely.

Catheter maintenance. Catheters will be inspected every 72 hrs for evidence of site infection (erythema around catheter, purulent drainage, swelling tenderness over catheter). Every 72 hrs (or sooner if necessary) the dressing will be removed and the exit site will be re-prepped with povidone-iodine. All fluids, medications, etc. administered through each lumen will be documented.

Catheter types. The inventors contemplate using different types of catheters. For example, control catheters consist of triple lumen polyurethane catheters and single lumen polyurethane catheters will be tested among several others. The test catheters will be identical to the control catheters in appearance, but they will be coated with the antiseptics of the invention, for example, Gendine.

Trial design. The trial is a prospective randomized design. The patient, the health care worker inserting the catheter, the microbiologist culturing the catheter, and the evaluator will be blinded as to whether the catheter is coated or not coated with the antiseptics of the invention. They will, however, be identifiable by an assigned code number. After informed consent has been obtained a catheter will be pulled out of a box containing 6 test and control catheter placement trays. The boxes will consist of either triple or single lumen catheters and will be labeled as such. The trays will be placed in the boxes such that test and control catheters will alternate from top to bottom. Each box will contain 3 test and 3 control catheters. The unique identification number of the catheter will be recorded and will be included with the data analysis. Both the investigators and the patients will be blinded to the catheter identity throughout the study.

Statistical Considerations. Assuming a conservative baseline colonization and/or infection rate of at least 20% for central venous catheters, randomizing 75 patients to each arm would allow one to detect a change in catheter-related infection rates from 20% to 5% one sided significance and 80% power. If, after entering 150 patients, the infection rate in the test arm has dropped by 50% (that is from 20% to 10%) then the study will be expanded to include 400 patients (200 in each arm). Using the selection criteria described above, the inventors estimate that they will test about 40 patients each month. Aiming for a total of 150 evaluable patients the study will be completed in approximately 6 months.

Termination of Study. Patients will be kept on study until the catheter is removed. The indication for catheter removal will be documented for each catheter. These include but are not limited to:

-   -   1. Catheter no longer needed     -   2. Catheter leaks     -   3. Bleeding around catheter     -   4. Catheter thrombosis     -   5. Catheter insertion site infection or sepsis     -   6. Positive blood cultures that are thought to be clinically         significant (i.e., associated fever, increased WBC) and no other         site of infection is identifiable.         When the patient becomes febrile, blood will be withdrawn         simultaneously through the lumen of the catheter and peripheral         vein for quantitative blood culture. At the time of catheter         removal, the catheter will be removed under aseptic conditions         and the tip and intracutaneous segments saved for culturing         using the roll plate and sonication quantitative catheter         culture technique. At the time of removal each lumen will be         marked as to its prior use (hyperalimentation).

Patient Evaluation—Pre-Insertion. Pertinent history will be taken and physical examination will be done regarding inclusion and exclusion criteria. Demographic data as well as details pertaining to underlying malignancy, treatment and antimicrobial treatment (including antimicrobial prophylaxis for infections in general in patients with hematologic malignancies) will be recorded. Investigational nature of study will be explained and informed consent will be obtained from patient. Pregnancy tests (serum or urine) will be obtained on all female patients with child bearing potential. If the test is positive, the patient will be excluded.

Initial catheterization procedure details will be recorded including catheter type, site and date of placement; difficulty of insertion, and complications if any. The difficulty of insertion will be determined by noting the following (a) number of attempts to insert the catheter (b) time spent during insertion (c) malpositioning and repositioning of a catheter.

Patient Evaluation—Post-Insertion. All patients will be monitored until the catheter is removed. Catheter site evaluation will be undertaken every 72 hrs with the change of dressing. Special attention will be given to erythema, infiltration, pain, tenderness, swelling, suppuration, palpable cord in vessel, tissue warmth, lymphangitis or phlebitis. Details pertaining to chemotherapy, antineoplastic and antimicrobials, will be recorded. Catheter usage as for agents that might cause sclerosis of the vessel involved, hyperalimentation, blood and blood products administration, and drawing of blood will be noted. The catheter insertion site will be recorded on every patient. In addition, events of repositioning the catheter after displacement will be recorded. Microbiologic evaluation of insertion site will be undertaken in the form of site cultures if suppuration is present. If catheter related septicemia is suspected, blood cultures will be drawn simultaneously through catheter and by peripheral venipuncture. Another set of cultures will be drawn 24 hours later. If thrombophlebitis is suspected venous flow study of involved vessel will be done. If line related infection is suspected (including in patients with fever of unknown origin) or septicemia is documented, catheter will be changed over guide wire and distal as well as the proximal 5-7 cm of the catheter will be evaluated for semiquantitative cultures by the inventors. The purpose of this procedure is diagnostic and not therapeutic. It will attempt to make a definitive diagnosis of catheter related infection by isolating the organism from the catheter using quantitative techniques.

End of Evaluation. When it is decided to withdraw the line, the catheter will be evaluated by the inventors for quantitative cultures. In addition, a quantitative blood culture will be drawn through the CVC lumen if the lumen is patent and peripherally if the patient is febrile.

Catheter Assessment:

1. Catheter tunnel infection: Either the proximal and/or the distal catheter segments growing >15 colonies by the roll-plate culture technique or >100 colonies by the sonication culture technique.

2. Catheter exit site infection: development of lymphangitis, purulence or two of the following: erythema, tenderness, induration or warmth.

3. Catheter related septicemia: Recovery of same organism from catheter segment and blood without any other identifiable source for the septicemia. The catheter should grow at least 15 colonies of the organism by roll plate or at least 100 colonies by sonication. The patient should have clinical manifestation of sepsis (fever, chills or sudden hypotension).

4. Catheter-related infection: any of the conditions defined above would be considered as catheter-related infection.

Success will be measured if there is no catheter related infection and failure will be indicated by the presence of a catheter related infection.

Adverse Reactions. All patients will be monitored for an unexpected adverse reaction (e.g., increased inflammation, phlebitis) associated with the coated catheter, using a statistical sequential test method. The study will be stopped if major adverse reaction is identified. Otherwise, the study will continue until 75 patients in each group have been enrolled.

Example 3 “Instant Dip Method”

Materials and Methods. One cm segments of either ETT or UC were dipped in GND solution and immediately removed, followed by overnight drying. Segments were then washed and left to dry in a fume hood.

Anti-microbial activity of GND-ETT and GND-UC segments was assessed by modified Kirby-Bauer method. Segments were embedded in Mueller Hinton agar plates inoculated with one of the following organisms: Candida albicans (CA), vancomycin resistant enterococci (VRE), E. coli (EC), Candida parapsilosis(CP), methicillin resistant S. aureus (MRSA) or Pseudomonas aeruginosa (PS). Plates were incubated at 37° C. Zones of inhibition (ZOI) created by impregnated segments were measured in mm.

GND-ETT and GND-UC were immersed in sterile pooled bronchoalveolar lavage (BAL) or urine, respectively, and incubated at 37° C. BAL and urine were changed weekly and ZOI were determined in duplicate at weekly intervals.

Biofilm was formed on segments of GND-UC and GND-ETT. Controls used for the GND-UC were silver hydrogel UC and control uncoated UC, and for the GND-ETT, control uncoated ETT was used. A modification of a method previously published by Kuhn et al. (2002) was used to form biofilm on device segments. Device segments were incubated in donor calf serum at 37° C. for 24 hrs. Serum was replaced with standard suspension of bacteria (1×10⁵ CFU/ml) and incubated for 24 hrs. Device segments were washed with saline to remove free-floating bacteria. Device segments were then placed into saline solution, sonicated for 15 min. and vortexed. 100 μl of the solution was plated on an agar dish and incubated at 37° C. for 24 hrs. Colony forming units (CFU) were recorded. CFU of 5,000 represented 5,000 or more.

Cytotoxicity testing was performed using the USP standard minimum essential media (MEM) elution test against L929 mouse fibroblast cells.

Results. The efficacy and durability of gendine-coated urinary catheters (GND-UC), prepared by instant dip into gendine-containing solution, was evaluated. GND-UC produced a baseline ZOI of 23 mm against Candida albicans (CA), 20 mm against vancomycin resistant enterococci (VRE) and 18 mm against E. coli (EC) (FIG. 1).

The efficacy and durability of gendine-coated endotracheal tubes (GND-ETT), prepared by instant dip into gendine-containing solution, was evaluated. GND-ETT produced a baseline ZOI of 32 mm against Candida parapsilosis(CP), 28 mm against methicillin resistant S. aureus (MRSA) and 26 mm against E. coli (EC) (FIG. 2).

Bacterial adherence to urinary catheters, prepared by instant dip into gendine-containing solution, was evaluated. There was a significant reduction (P=0.001) in the number of colonies of methicillin resistant S. aureus (MRSA), Candida parapsilosis(CP), and E. coli (EC) adhering to gendine-coated segments in comparison to control uncoated segments and silver hydrogel UC (FIG. 3).

Bacterial adherence to endotracheal tubes (ETT), prepared by instant dip into gendine-containing solution, was evaluated. There was significant reduction in the number of CFU isolated from the surface of GND-ETT in comparison to control uncoated ETT (P=0.003 for methicillin resistant S. aureus (MRSA), Candida parapsilosis(CP), and E. coli (EC); P=0.023 for Pseudomonas aeruginosa (PS) (FIG. 4).

All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

REFERENCES

The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.

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1. A method for coating or impregnating a medical device with an antiseptic composition comprising: a) contacting said medical device for no more than about 10 minutes with a solvent comprising a basic reagent and a dye; and b) drying the device.
 2. The method of claim 1, wherein said contacting occurs for no more than about 5 minutes.
 3. The method of claim 1, further comprising the step of washing off excessive solvent from the medical device.
 4. The method of claim 1, wherein the medical device is contacted with the solvent for about 1 minute.
 5. The method of claim 1, wherein the medical device is immersed in the solvent and immediately removed.
 6. The method of claim 1, wherein the medical device is sprayed with the solvent.
 7. The method of claim 1, wherein the basic reagent and the dye are bonded.
 8. The method of claim 7, wherein the basic reagent and the dye are bound ionically.
 9. The method of claim 7, wherein the basic reagent and the dye are bound covalently.
 10. The method of claim 1, wherein the dye is a triarylmethane dye.
 11. The method of claim 1, wherein the dye is a monoazo dye.
 12. The method of claim 1, wherein the dye is a diazo dye.
 13. The method of claim 1, wherein the dye is an indigoid dye.
 14. The method of claim 1, wherein the dye is a xanthene dye.
 15. The method of claim 1, wherein the dye is an anthraquinone dye.
 16. The method of claim 1, wherein the dye is a quinoline dye.
 17. The method of claim 1, wherein the dye is gentian violet or crystal violet, ethyl violet, brilliant green, an FD&C dye, or a D&C dye.
 18. The method of claim 17, wherein the FD&C dye is Blue No. 1 or Green No.
 3. 19. The method of claim 10, wherein the triarylmethane dye is gentian violet.
 20. The method of claim 11 wherein the monoazo dye is FD&C Yellow No. 5 or D&C Yellow No.
 6. 21. The method of claim 12, wherein the diazo dye is D&C Red No.
 17. 22. The method of claim 13, wherein the indigoid dye is FD&C Blue No.
 2. 23. The method of claim 14, wherein the xanthene dye is FD&C Red No.
 3. 24. The method of claim 15, wherein the anthraquinone dye is D&C Green No.
 6. 25. The method of claim 16, wherein the quinoline dye is D&C Yellow No.
 1. 26. The method of claim 1, wherein the basic reagent is a guanidium compound, a biguanide, a bipyridine, a phenoxide antiseptic, an alkyl oxide, an aryl oxide, a thiol, a halide, an aliphatic amine, EDTA or an aromatic amine.
 27. The method of claim 26, wherein the basic reagent is a guanidium compound.
 28. The method of claim 27, wherein the guanidium compound is chlorhexidine.
 29. The method of claim 27, wherein the guanidium compound is alexidine.
 30. The method of claim 27, wherein the guanidium compound is hexamidine.
 31. The method of claim 26, wherein the basic reagent is a bipyridine.
 32. The method of claim 31, wherein the bipyridine is octenidine.
 33. The method of claim 26, wherein the basic reagent is a phenoxide antiseptic.
 34. The method of claim 33, wherein the phenoxide antiseptic is clofoctol.
 35. The method of claim 33, wherein the phenoxide antiseptic is chloroxylenol.
 36. The method of claim 33, wherein the phenoxide antiseptic is triclosan.
 37. The method of claim 1, wherein the antiseptic composition is gendine, genlenol, genlosan, or genfoctol.
 38. The method of claim 1, wherein the medical device is composed of latex, latex-silicone or silicone.
 39. The method of claim 1, wherein the medical device is composed of polyurethane.
 40. The method of claim 1, wherein the medical device is composed of polyvinyl chloride.
 41. The method of claim 1, wherein the solvent comprises methylene chloride, methanol, or a combination thereof.
 42. A medical device coated or impregnated with an antiseptic composition by a process comprising: a) contacting said medical device for no more than about 10 minutes with a solvent comprising a basic reagent and a dye; and b) drying the device. 43-85. (canceled) 